The blood-brain barrier (BBB) is a specialized system that protects the brain from harmful substances in the blood and helps maintain balance. A key part of the BBB is a carbohydrate-rich layer called the glycocalyx, which comprises proteoglycans, glycoproteins, and glycolipids.
This layer covers the inner surface of blood vessels in the brain and acts as the first line of defense between the blood and the brain.
However, its exact composition and how it helps the BBB function in healthy and diseased conditions remains unknown.
What if an important clue to brain aging has been before us all along?
Neuroscience has typically focused on proteins and DNA, but a team of Stanford researchers decided to examine sugars—specifically, the complex sugar chains that cover our cells like protective armor.
They found that changes in these sugar coatings on brain cells could be crucial to understanding cognitive decline and diseases like Alzheimer’s.
In a study with aging mice, Shi discovered significant changes in the sugary coating (glycocalyx) on cells that form the blood-brain barrier. This barrier protects the brain by filtering harmful substances and allowing essential nutrients in.
Shi compares the glycocalyx to a forest: in young, healthy brains, it’s lush and thriving, but in older brains, it becomes sparse and degraded.
These age-related changes weaken the blood-brain barrier, making it leaky. As a result, harmful molecules can enter the brain, potentially causing inflammation, cognitive decline, and neurodegenerative diseases.
Wyss-Coray, a professor of neurology, says this research opens up a new field of study on how the aging brain loses its resilience.
While Wyss-Coray’s lab has studied how aging affects the blood-brain barrier, Shi’s project was the first to examine how aging impacts its sugary coating, the glycocalyx.
The key cellular mechanism driving Alzheimer’s disease unraveled
The results were surprising: in older mice, the sugar-coated proteins called mucins, a key part of the glycocalyx, were significantly reduced. This thinning of the glycocalyx made the blood-brain barrier leakier and increased inflammation in the brain.
When the team reintroduced these important mucins in older mice, restoring a more “youthful” glycocalyx, they improved the blood-brain barrier’s integrity, reduced brain inflammation, and improved cognitive function.
Shi explained that “modulating glycans has a major effect on the brain – both negatively when these sugars are lost in aging, and positively when they are restored.” This discovery opens new possibilities for treating brain aging and related diseases.
The study raises new questions. Traditionally, the glycocalyx is seen as a passive barrier that blocks harmful substances from entering cells. However, its sugars might play a more active role in brain aging.
Scientists usually focus on nucleic acids and proteins to understand how biological processes are controlled, but they might be overlooking the role of sugar molecules. Bertozzi explains that sugars add a complexity layer that allows fine-tuning biological systems. This is especially true in the brain, where many sugar molecules are unique, yet their roles in brain aging and disease are mostly unexplored.
Shi’s expertise in both chemistry and biology enabled her to solve a problem that neither lab could tackle alone. This study also brought together two interdisciplinary institutes: Sarafan ChEM-H and the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute.
A new mechanism for crossing the blood-brain barrier
Many questions remain about the glycocalyx, such as why it declines with age and whether similar changes occur in humans. Bertozzi notes that studying human brains is difficult, but understanding whether these mechanisms also occur in humans is crucial for developing therapies.
The study offers new opportunities to address neurodegenerative diseases like Alzheimer’s, which Shi is particularly interested in. By identifying the molecular pathways behind glycocalyx changes, the team hopes to find therapeutic targets that could slow or reverse disease progression.
Shi, who will soon start her own lab at the Rowland Institute at Harvard, plans to expand this research to understand glycans’ roles in neurodegeneration and explore new treatments.
Beyond aging and neurodegeneration, the findings are important for delivering drugs to the brain. The blood-brain barrier is tough to penetrate, making it hard to treat many neurological diseases. By understanding the glycocalyx’s role, scientists may find better ways to get medicines into the brain, offering hope for conditions like multiple sclerosis and brain cancer.
This work is a first step into a new field. As Shi says, “I’m excited to unlock the secrets of the glycocalyx in brain aging and neurodegeneration and discover how we can harness its potential to improve brain health.”
Journal Reference
- Shi, S. M., Suh, R. J., Shon, D. J., Garcia, F. J., Buff, J. K., Atkins, M., Li, L., Lu, N., Sun, B., Luo, J., To, N., Cheung, T. H., McNerney, M. W., Heiman, M., & Bertozzi, C. R. (2025). Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease. Nature, 1-10. DOI: 10.1038/s41586-025-08589-9
